Premature or preterm delivery of otherwise normal babies is a problem throughout the world, in both developed and developing countries. In fact, delivery of infants before the completion of 37 weeks of gestation is the leading cause of neonatal morbidity and mortality in the United States, (McCormick, 1985, New Engl. J. Med. 312:82-90), where the incidence of such deliveries has hovered around 7-9% for many years (McCormack, "Trends in Rates of Low Birthweight in the United States," In Berendes HW, Kessel S, Yaffe S, (eds.) Advances In The Prevention Of Low Birthweight, Washington, D.C.: National Center for Education in Maternal and Child Health, 3-11). Studies have shown that preterm, neonates account for more than half, and perhaps as much as 75%, of the mortality and morbidity among newborns who do not have congenital abnormalities (Rush et al., 1976, Brit. Med. J. 2:965-958). Although various intervention programs have claimed success in reducing the number of preterm deliveries, the results of these studies have been difficult to reproduce or sustain (Creasy et al., 1990, Obstet. Gynecol. 76:Suppl: 2S-4S). Thus, as perinatal mortality and morbidity stemming from other causes have decreased, the relative magnitude of the problem of preterm delivery has increased, despite significant improvements in neonatal care (Creasy, 1991, New Engl. J. Med. 325(10):727-728).
The medical profession has acknowledged that preventing preterm labor or rupture of fetal membranes is far more desirable than dealing with the problem after the fact. A solution to the problem has been exacerbated because preterm birth is a multifaceted event having different causes. Most of the current approaches to the prevention of preterm birth rely in part on risk-scoring systems to identify a group of women to whom special attention can be directed. These rely on such factors as obstetrical history, demographic factors, and premonitory symptoms (Main et al., 1985, Am. J. Obstet. Gynecol. 151:892-898). However, these approaches have been roundly criticized as being neither sensitive nor specific. For example, application of these methods to multiple pregnancies, including bed rest in pregnancies with twins, has been shown to be of little value (MacLennan et al., 1990, Lancet 15 335:267-269). Current treatment regimens have also been frequently hampered by an advance stage of labor or the inability to distinguish between irrelevant contractions and true preterm labor (Lockwood et al., 1991, New Engl. J. Med. 325(10):669-674). Thus, effective preventative measures have been essentially unavailable, largely because of the inability to predict the problem with enough certainty to warrant enrolling patients in a trial of preventative approaches (Creasy et al., supra).
A majority of research has focused on identifying a biochemical marker predictive of spontaneous preterm labor or premature rupture of the fetal membranes. Various candidates for biochemical markers of preterm delivery, e.g., plasma estradiol-17 beta, progesterone, and C-reactive protein, have not withstood rigorous scrutiny (Lockwood, supra). Lockwood et al. studied fetal fibronectin as a marker candidate, based upon the previous identification of this ubiquitous plasma and extracellular matrix protein in amniotic fluid and placental tissue (Matsuuia et al., 1985, Proc. Natl. Acad. Sci. USA 82:6517-6521). The hypothesis put forth by Lockwood et al. centers on the fact that mechanical or inflammatory-mediated damage to the fetal membrane before preterm delivery results in the release of fibronectin into the cervix and vagina. However, these authors recognized that this test was not as accurate predictor of preterm delivery. In addition, others (Creasy et al., 1990, Obstet. Gynecol. 76:Suppl: 2S-4S) supported the fact that the presence of fetal fibronectin was not indicative of premature fetal membrane rupture.
The chorioamniotic membranes are essentially connective tissue structures. Since collagen determines the tensile strength of fibrous connective tissue, there has been considerable interest in investigating collagen biochemistry in the setting of premature fetal membrane rupture (Romero et al., May 1993, Contemp. OB/GYN:33-44). Some investigators have detected low collagen content in membranes that have ruptured prematurely as compared with normal membranes, and suggested that the tensile property of the amniotic membranes which rupture must be lower than the tensile property in normal membranes (Skinner, et al., 1981, Obstet. Gynecol. 57:487-489). However, other groups have found no difference in the connective tissue collagen content in prematurely ruptured fetal membranes (Al-Zaid et al., 1980, Br. J. Obstet. Gynecol. 87:227-229; Evaldson et al., 1987, Gynecol. Obstet. Invest. 29:92-94). There have been yet other reports of high levels of collagenolytic activity in prematurely ruptured fetal membranes and in the serum of women with preterm labor (Vadillo-Oretega, 1990, Obstet. Gynecol. 75:84-88). However, the precise mechanism underlying these biochemical changes has remained unknown (Katsura et al., 1989, FEBS Letters 244 (2):315-318); So et al., 1992, Biol. Reprod. 46:772-78). Enzymes capable of degrading collagen have been previously described as products of cultured cells derived from fetal membranes (So et al., 1993, Acta. Obst. Gynaec. (Jpn) 45(3):227-233).
The immunocytochemical detection of collagenase (MMP-2) in fetal membranes was reported in Fernandez et al. (1992, Lab. Invest. 66:572-579). The enzyme family known as matrix metalloproteinases (MMPs) has been implicated in many normal tissue remodeling processes such embryonic development, postpartum involution of the uterus, bone and growth plate remodeling, ovulation, and wound healing, as well as pathological conditions such as arthritis, tumor invasion and metastasis (Woessner, 1991, FASEB J. 5:2145-2154.) While these enzymes may act on certain common substrates such as denatured collagen (gelatin) in vitro, they undoubtedly have specific natural substrates in vivo which account for their distinct roles in specific cellular processes. The enzymes described by So et al. (supra), namely MMP-1 and MMP-3, have not been correlated with structural changes in fetal membranes.
Despite the advances which have been made in understanding fetal development and in managing prenatal care, there remains a long felt need in the art for a specific and reliable biochemical marker with which to predict premature fetal membrane rupture. The identification of a marker of premature fetal membrane rupture would serve as a means of identifying and developing compositions capable of delaying premature fetal membrane rupture for which there is also a long felt need.